Human Retroviral gag- and gag-pol-like Proteins Interact with the Transforming Growth Factor-β Receptor Activin Receptor-like Kinase 1

Lux, Andreas; Beil, Christian; Majety, Meher; Barron, Suzanne; Gallione, Carol J.; Kuhn, Hella-Monika; Berg, Jonathan; Kioschis, Petra; Marchuk, Douglas A.; Hafner, Mathias

doi:10.1074/jbc.m409197200

Cited by 57 publications

(95 citation statements)

References 52 publications

(38 reference statements)

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“…PEG10 encodes a protein with distant similarity to retroviral gag-pol proteins and is expressed most strongly in the developing placenta but also in certain normal adult organs including the heart and lung (2,3). The PEG10 gene is activated in a variety of human cancers and data from manipulating the expression of this gene in cancer cell lines, both in prior work (5,8) and in the current study, indicate that it has a positive role in cell proliferation. Given the parental ''direction'' of its imprinting (paternal allele active), this growth-positive role for PEG10 would be predicted by the genomic conflict or kinship theory of imprinting (22).…”

Section: Discussionmentioning

confidence: 67%

“…PEG10 is also overexpressed in the embryonic form of biliary atresia, a disease associated with cell proliferation (7). Additional reports have suggested that PEG10 protein may act by blocking transforming growth factor h (TGF-h) signaling in epithelial cancers via binding to TGF-h receptor II (8) or by blocking the apoptotic factor SIAH1 (5). It was recently found that specific chemokines induce PEG10 in normal B-lymphocytes and in B-cell leukemias, correlating with increased cellular resistance to apoptosis (9).…”

Section: Introductionmentioning

confidence: 99%

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PEG10 Is a c-MYC Target Gene in Cancer Cells

Margolin

Salas

et al. 2006

Cancer Research

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The product of the imprinted gene paternally expressed gene-10 (PEG10) has been reported to support proliferation in hepatocellular carcinomas, but how this gene is regulated has been an open question. We find that MYC knockdown by RNA interference suppresses PEG10 expression in Panc1 pancreatic carcinoma and HepG2 hepatocellular carcinoma cells and that knockdown of PEG10 inhibits the proliferation of Panc1, HepG2, and Hep3B cells. Conversely, PEG10 was up-regulated by inducing c-MYC expression in a B-lymphocyte cell line. Chromatin immunoprecipitation from Panc1 cells showed c-MYC bound to an E-box-containing region in the PEG10 first intron and site-directed mutagenesis showed that the most proximal E-box is essential for promoter activity. In a mouse mammary tumor virus (MMTV)-MYC transgenic mouse model of breast cancer, most but not all of the mammary carcinomas had strongly increased Peg10 mRNA compared with normal mammary gland. By immunohistochemistry, normal human breast and prostate epithelium was negative for the major isoform [reading frame-1 (RF1)] of PEG10 protein, but this cytoplasmic protein was strongly expressed in a subset of breast carcinomas in situ and invasive ductal carcinomas (f30%) and in a similar percentage of prostate cancers. As in the mouse model, we found positive, but not absolute, correlations between PEG10 and c-MYC in tissue arrays containing 161 human breast cancers (P < 0.002) and 30 prostate cancers (P = 0.014). Immunostaining of human placenta showed PEG10 and c-MYC proteins coexpressed in proliferating cytotrophoblast and coordinately lost in postmitotic syncytiotrophoblast. These findings link cancer genetics and epigenetics by showing that a classic protooncogene, MYC, acts directly upstream of a proliferationpositive imprinted gene, PEG10. (Cancer Res 2006; 66(2): 665-72)

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

PEG10 Is a c-MYC Target Gene in Cancer Cells

Margolin

Salas

et al. 2006

Cancer Research

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“…2, B and C, lanes 2). This difference, noted previously for ORF1 (15), suggests the presence of post-translational modification (note that the His and FLAG tags add less than 2 kDa to each ORF).…”

Section: Resultsmentioning

confidence: 99%

“…Both ORF1 and ORF2 antibodies detected three separate protein fragments suggesting the presence of multiple proteolytic cleavage sites in the PEG10 protein. There is a possible aspartic protease cleavage site at the junction between ORF1 and ORF2 (15), and the PEG10 cleavage products of ϳ51 and ϳ40 kDa may arise from cleavage at this site. This would result in cleavage of PEG10 "Gag" from "Gag-Pol," consistent with what is observed during the processing of HIV-1 and LTR retrotransposons (37).…”

Section: Discussionmentioning

confidence: 99%

“…Although mRNAs are found in these and other tissues, PEG10 protein expression in vivo is yet to be documented apart from the identification of PEG10 ORF1 in mid-term human placenta (14). Expression of mouse PEG10 by in vitro translation (11) and human PEG10 in cell culture (15) has shown that PEG10 contains all the functional elements for expression and frameshifts with 15-30% efficiency in these settings. The phenotype of a mouse PEG10 deletion knock-out was embryonic lethal by 10.5 days post-coitus (dpc) due to defects in placental formation (16).…”

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confidence: 99%

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Mammalian Gene PEG10 Expresses Two Reading Frames by High Efficiency –1 Frameshifting in Embryonic-associated Tissues

Clark¹,

Jänicke²,

Gottesbühren³

et al. 2007

Journal of Biological Chemistry

113

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Paternally expressed gene 10 (PEG10) is a mammalian gene that is essential for embryonic development in mice. The gene contains two overlapping open reading frames (ORF1 and ORF2) and is derived from a retroelement that acquired a cellular function. It is not known if both reading frames are required for PEG10 function. Synthesis of ORF2 would be possible only if programmed ؊1 frameshifting occurred during ORF1 translation. In this study the frameshifting activity of PEG10 was analyzed in vivo, and a potential role for ORF2 was investigated. Phylogenetic analysis demonstrated that PEG10 is highly conserved in therian mammals, with all species retaining the elements necessary for frameshifting as well as functional motifs in each ORF. The frameshift site of PEG10 was highly active in cultured cells and produced the ORF1-2 protein. In mice, endogenous ORF1 and an ORF1-2 frameshift protein were detected in the developing placenta and amniotic membrane from 9.5 days post-coitus through to term with a very high frameshift efficiency (>60%). Mutagenesis of the active site motif of a putative protease within ORF2 showed that this enzyme is active and participates in post-translational processing of PEG10 ORF1-2. Both PEG10 proteins were also detected in first trimester human placenta. By contrast, neither protein expression nor frameshifting was detected in adult mouse tissues. These studies imply that the ORF1-2 protein, synthesized utilizing the most efficient ؊1 frameshift mechanism yet documented in vivo, will have an essential function that is intrinsic to the importance of PEG10 in mammals.

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Turning junk into gold: domestication of transposable elements and the creation of new genes in eukaryotes

2006

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Autonomous transposable elements, generally considered as junk and selfish, encode transposition proteins that can bind, copy, break, join or degrade nucleic acids as well as process or interact with other proteins. Such a repertoire of activities might be of interest for the host cell. There is indeed substantial evidence that mobile DNA can serve as a dynamic reservoir for new cellular functions. Transposable element genes encoding transposase, integrase, reverse transcriptase as well as structural and envelope proteins have been repeatedly recruited by their host during evolution in most eukaryotic lineages. Such domesticated sequences protect us against infections, are necessary for our reproduction, allow the replication of our chromosomes and control cell proliferation and death; others are essential for plant development. Many new candidates for domesticated sequences have been revealed by sequencing projects. Their functional analysis will uncover new aspects of evolutionary alchemy, the turning of junk into gold within genomes.

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Human Retroviral gag- and gag-pol-like Proteins Interact with the Transforming Growth Factor-β Receptor Activin Receptor-like Kinase 1

Cited by 57 publications

References 52 publications

PEG10 Is a c-MYC Target Gene in Cancer Cells

PEG10 Is a c-MYC Target Gene in Cancer Cells

Mammalian Gene PEG10 Expresses Two Reading Frames by High Efficiency –1 Frameshifting in Embryonic-associated Tissues

Turning junk into gold: domestication of transposable elements and the creation of new genes in eukaryotes

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